Preparation method of mirabegron related substance and intermediate thereof

Abstract

The invention relates to the technical field of medicine synthesis, and provides a preparation method of a mirabegron related substance and an intermediate thereof. The preparation method comprises the following steps of: firstly, carrying out esterification reaction on phenethyl alcohol and a sulfonyl chloride compound, and then carrying out condensation on the obtained phenethyl alcohol sulfonate and 4-nitrophenylethylamine to obtain the mirabegron related substance intermediate. According to the invention, phenethyl alcohol is used as an initial raw material, is harmless to human body and environment, and has the advantages of good safety, wide source and low cost, and the yield and purity of the product are high. After the mirabegron related substance intermediate is obtained, the mirabegron related substance is obtained through reduction and condensation. The steps are simple, and the yield and purity of the product are high. By adopting the method disclosed by the invention, the high-purity mirabegron related substance and the intermediate thereof can be prepared. When the mirabegron related substance or the intermediate thereof is used as an impurity reference substance for mirabegron quality control, impurities generated in mirabegron synthesis can be effectively identified, and the related substance is quantitatively controlled, so that the detection cost of enterprises is reduced, and a technical guarantee is provided for guaranteeing the drug quality.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of mirabegron related substances and intermediates thereof. Background technique [0002] Mirabegron, the chemical name is (R)-2-(2-aminothiazol-4-yl)-N-(4-{2-[(2-hydroxy-2-phenylethyl)amino ] ethyl} phenyl) acetamide, structural formula as shown in formula A. Mirabegron is a selective β3 adrenoceptor agonist developed by Japan's Astellas Pharmaceutical Company for the treatment of overactive bladder including urinary incontinence, urgency and frequency. It was launched in Japan in September 2011 under the product name Betanis. In June 2012, it was approved by the US FDA for the treatment of overactive bladder in adults. It was approved by the European Medicines Agency (EMA) in December 2012 and launched in 2017. It entered China in December 2020. By 2020, the global sales will exceed 1.4 billion US dollars, and the market prospect is broad. [0003...

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Problems solved by technology

[0009]This method uses phenylacetic acid as a raw material, which belongs to the second category of controlled products among precursor chemicals, and its purchase, use, and storage have strict requirements and Difficult to obtain; the amount of borane-tetrahydrofuran solution solvent used in the second amide reduction reaction is too large, has a foul smell, is sensitive to moisture, reacts violently with water and emits flammable gases, can form explosive peroxides, and is harmful to eyes, Respiratory system and skin are irritated, which is not good for operators and ecological environment; and this method has disadvantages such as long synthetic route, low yield and high cost

[0010]In addition, some literature reports use haloethylbenzene as the starting material to synthesize the dehydroxylation impurity, the synthetic route is similar to Scheme 2, and haloethylbenzene is Eyes, respiratory system and skin are all irritating to a certain extent, and there are also problems that are unfavorable to operators and the ecological environment. When using haloethylbenzene as the starting material, haloethylbenzene and 4-nitrophenylethylbenzene The step yield of amine condensation reaction is low, only about 75%, and after the condensation reaction is completed, complex post-treatment is required, and there is a problem of cumbersome operation

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